Derivatives of 1,1,2,2-tetramethyl-1,2-bis-(2-fluoro-4-hydroxyphenyl)-ethane

ABSTRACT

Antitumor compounds corresponding to the following formula: ##STR1## in which the substituents R 1  and R 2  may be the same or different and represent hydrogen, an aminocarbonyl group, a C 1  -C 6  alkylaminocarbonyl group, a di-C 1  -C 6  -alkylaminocarbonyl group, the group PO(OH) 2 , a C 2  -C 8  alkanoyl group, a C 2  -C 8  halogen alkanoyl group or a C 3  -C 8  alkenoyl group, a process for their preparation, and their use in treating oestrogen-receptor-positive-tumors as well as the prostate carcinoma.

BACKGROUND OF THE INVENTION

The true antioestrogen,1,1,2,2-tetramethyl-1,2-bis-(4-hydroxyphenyl)-ethane (R. W. Hartmann,Eur. J. Cancer Clin. Oncol. 1983, 19 959), shows considerable affinityfor the oestrogen receptor (relative binding affinity=3.6). Thiscompound shows for example a strong effect as antioestrogen byinhibiting the oestrone- or oestradiol-stimulated uterus growth ofjuvenile mice and inhibits the growth of the mammary carcinoma inducedin rats (Sprague Dawley rats) by 7,12-dimethylbenzanthracene (DMBA), anexperimental tumor which is very similar in its behavior to the humanmammary carcinoma (MC).

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the following formula:##STR2## in which the substituents R₁ and R₂ may be the same ordifferent and represent hydrogen, an aminocarbonyl group, a C₁ -C₆alkylaminocarbonyl group, a di-C₁ -C₆ -alkylaminocarbonyl group, thegroup PO(OH))₂, a C₂ -C₈ alkanoyl group, a C₂ -C₈ halogen alkanoyl groupor a C₃ -C₈ alkenoyl group, a process for their preparation and theiruse in treating oestrogen-receptor-positive tumors.

Examples of C₁ -C₆ alkylaminocarbonyl are methylaminocarbonyl,ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl,butylaminocarbonyl, hexylaminocarbonyl. Examples of di-C₁ -C₆-alkylamino carbonyl groups are dimethylaminocarbonyl,diethylamino-carbonyl, methyl ethyl aminocarbonyl,diisopropylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl.Examples of C₂ -C₈ -alkanoyl groups are acetyl, propionyl, butyryl,valeroyl, hexanoyl, octanoyl. Examples of C₂ -C₈ halogen alkanoyl groupsare chloroacetyl, dichloroacetyl, trichloroactyl, bromoacetyl,iodoacetyl, alpha-chloropropionyl, beta-chloropropionyl,omega-chlorobutyryl, omega chlorohexanoyl. Examples of C₃ -C₈ alkenyloylgroups are acroyl, methacroyl, ethacroyl, crotonoyl.

The compounds are prepared by a process comprising in a compoundcorresponding to the following formula: ##STR3## in which R₃ is a C₁ -C₄alkyl group eliminating these two alkyl groups and optionally acylatingthe resulting compound of formula I, in which the two substituents R₁and R₂ are hydrogen, by the substituents R₁ and R₂ other than hydrogen,and optionally converting C₃ -C₈ halogen alkanoyl groups present in theresulting compounds into C₃ -C₈ alkenoyl groups by elimination ofhydrogen halide.

The compounds according to the invention surprisingly show aconsiderably increased affinity for the oestrogen receptor (relativebinding affinity of the compound according to Example 1=11) and show aconsiderably greater effect on the DMBA-tumor than the known compound.

The compounds according to the invention are antioestrogens and show astrong oestrogen-antagonistic effect, for example in the uterus weighttest in juvenile mice.

The compounds according to the invention show strong antitumor activityon oestrogen-receptor-positive tumors because they become concentratedin hormone-dependent tumors.

The compounds according to the invention are particularly suitable forthe treatment of hormone-dependent tumors, particularly thehormone-dependent mammary carcinoma. However, they are also suitable,for example, for the treatment of the prostate carcinoma because theyreduce the weight of target organs (such as for example the seminalvesicle) in mice and considerably reduce the testosterone level. Anothervery important factor is that the antioestrogenic compounds according tothe invention show only minimal oestrogenic effects. With compoundscorresponding to formula I, in which R₁ and R₂ are not hydrogen atoms,the phase of metabolization to the water-soluble metabolite does notoccur. Accordingly, the half-life of these compounds is increased sothat their antitumor effect is long-lasting. The compounds of the typein question are particularly suitable for peroral administration or forapplication in slow-release form. As a water-soluble compound, thecompound of formula I in which R₁ and R₂ represent the group --PO(OH)₂is particularly suitable for intravenous application. The substituentsR₁ and R₂ are preferably the same. If one or both substituents R₁ and R₂contain alkyl groups or represent alkenoyl groups, halogen alkanoylgroups or alkenoyl groups, these groups may be linear or branched. Ifthe substituents R₁ and/or R₂ are C₂ -C₈ alkanoyl groups, these groupspreferably consist of from 1 to 4 carbon atoms. The groups in questionare in particular acetyl groups. If these alkanoyl groups containshalogen atoms, the halogen atoms may be situated at one or severalcarbon atoms; the halogen atoms (particularly chlorine and bromine) maynumber from 1 to 3. Examples of halogen alkanoyl groups are CHCl₂--CO,CH₂ Cl--CO, CCl₃ --CO--, CH₂ Cl--CH₂ --CO, CH₂ Br--CH₂ --CO, CHCl₂--CH₂ --CO--, CHBr₂ --CH₂ CO--, CH₂ Cl--CHCl--CO, CH₂ Br--CHBr--CO,CHCl₂ --CHCl--CO--, CH₂ Br--CHBr--CO--. If R₁ and/or R₂ represent C₃ -C₈alkenoyl groups, these groups consist in particular of from 3 to 6carbon atoms. In this case, the group in question is preferably the CH₂═CH--CO group (acroyl group).

The process according to the invention is carried out at a temperaturein the range of from -70° C. to +250° C.

The C₁ -C₄ alkyl groups (ether groups) are eliminated, for example, inthe absence of a solvent or in the presence of an inert solvent, such asboron tribromide, boron trifluoride, aluminium chloride, silicontetrachloride, aluminium tribromide, sodium ethylthiolate, (CH₃)₃SiCl+NaI, at temperatures of from -70° C. to 200° C. Suitable solventsfor elimination of the ether groups are, for example, aliphatichalogenated hydrocarbons, such as for example methylene chloride,aromatic hydrocarbons, such a benzene, toluene, xylene, halogenatedaromatic hydrocarbons, such as chlorobenzene, dichlorobenzenes,dimethylformamide, acetonitrile, nitrobenzene, carbon disulfide anddioxane.

Elimination of the ether groups may also be carried out usingconcentrated hydroiodic acid, hydrobromic acid (particularly in mixtureswith acetic acid and acetic acid anhydride), pyridine hydrochloride,sulfuric acid, trifluoroacetic acid, phosphoric acid, chloro-, methyl-,p-toluene sulfonic acid, methylmagnesium iodide in the presence orabsence of solvents at temperatures of from 20° C. to 250° C. Suitablesolvents for this method of elimination are, for example, aliphaticethers containing C₁ -C₆ alkyl groups, toluene and benzene.

The acylation step of the process according to the invention is carriedout with an acid corresponding to the formula R--OH, where R is anaminocarbonyl group, a C₁ -C₆ alkylaminocarbonyl group, a di-C₁ -C₆-alkylaminocarbonyl group, the group PO(OH)₂, a C₂ -C₈ alkanoyl group ora C₂ -C₈ halogen alkanoyl group, the acid in question preferably beingactivated. Where an activated acid is used for the acylation, it ispreferably selected from compounds corresponding to the formula R-X, inwhich R is as defined above and X represents a halogen atom, a group ofthe formula --OR', --SR' or a group of the formula --OSO₃ H or --OCO--R"where R' is a C₁ -C₆ alkyl group or, in the case of --OR' or --SR', alsoa phenyl group; a phenyl group substituted by one or more nitro groups,C₁ -C₄ alkoxy groups, C₁ -C₄ alkyl groups or halogen atoms (chlorine,fluorine, bromine); a cyanomethyl group; or a carboxymethyl group, andwhere R" is a straight-chain or branched C₁ -C₇ alkyl group, a C₁ -C₇halogen alkyl group, a C₁ -C₆ alkoxy group, a phenoxy group or abenzyloxy group; R may also represent the group COCl, POCl₂ or the cyanogroup where X is halogen and, in the case of COCl, amination is carriedout by reaction in the usual way with NH₃, a C₁ -C₆ alkylamine or adi-C₁ -C₆ -alkylamine and in the case of POCl₂ or the cyano group,hydrolysis is carried out with a mineral acid (sulfuric acid orhydrochloric acid or a mixture of both acids). This hydrolysis reactionis carried out, for example, in aqueous medium at temperatures of from50° C. to 80° C.

Where X is a halogen atom, the halogen atom in question is preferablychlorine, bromine or iodine; where R' or R" is an alkyl group, a halogenalkyl group or an alkoxy group, these groups are preferably of lowmolecular weight and consist of from 1 to 4 carbon atoms.

The acylation step is carried out, for example, in a standard solvent orsuspending agent, such as water, optionally with addition of a solutionpromoter (for example lower aliphatic alcohols, e.g. ethanol orisopropanol, lower aliphatic ketones, e.g. acetone, dimethylformamide)or inert media. Suitable solvents or suspending agents are, for example,low molecular weight aliphatic ethers (for example 4 to 10 carbon atoms,e.g. diethyl ether), low molecular weight aliphatic ketones (for example3 to 6 carbon atoms, e.g. acetone, methyl ethyl ketone); saturatedcyclic ethers, such as tetrahydrofuran, dioxane, low molecular weightsaturated chlorinated and fluorinated hydrocarbons containing from 1 to5 carbon atoms, the individual carbon atoms optionally being substitutedonce or several times (2 to 3 times) by chlorine and/or fluorine, suchas chloroform, methylene chloride, dichlorodifluoroethane, aromatichydrocarbons optionally substituted by chlorine or bromine, such asbenzene, toluene, xylene, chlorobenzene, dimethylformamide,dimethylsulfoxide, tetramethylurea, pyridine, N-methyl-pyrrolidone.Mixtures of these solvents may of course also be used.

The acylation is carried out, for example, at temperatures of from 0° to200° C. and preferably at temperatures of from 15° to 150° C.

In many cases, particularly where X is a halogen atom or represents thegroup --OCOR", the presence of an acid-binding agent, such as alkalihydroxide, e.g. sodium hydroxide, potassium hydroxide, alkalicarbonates, e.g. sodium carbonate, alkali hydrogen carbonates, e.g.sodium bicarbonate, alkali acetates, e.g. sodium acetate, alkaline earthcarbonates, e.g. calcium carbonate, trialkylamines, e.g. triethyl amine,dialkylamines, e.g. diethylamine, pyridine and the like is advisable.The acid-binding agent may also be used simultaneously as solvent eitheron its own or in admixtures with other standard media (for examplepyridine).

The acylation may also be carried out by initially preparing an alkalicompound of the compound to be reacted by reacting it with an alkalimetal, alkali hydride or alkali amine (particularly sodium or sodiumcompounds) in an inert solvent, such as dioxane, dimethylformamide,benzene or toluene at temperatures of from 0° to 150° C. and, forexample, subsequently adding the acylating agent (compound R--X,R=halogen).

Where the free acid R--OH is used, it has to be activated by thepresence of condensation agents, such as dicyclohexylcarbodiimide,tetraethylprophosphite, 5-(3'-sulfonephenyl)-ethylisooxazole, sulfurousacid-bis-alkylamide (for example SO[N(CH₃)₂ ]₂, N,N'-carbonyldiimidazole and so on (Organic Reactions, Volume 12, 1962, pages 205 and239).

Compounds corresponding to formula I, in which one or both substituentsR₁ and R₂ represent a C₃ -C₈ alkenoyl group, may also be obtained fromcorresponding compounds I in which one or both of these substituentsis/are a C₃ -C₈ alkanoyl group containing a chlorine or bromine atom(preferably in the β-position) by eliminating the halogen atom with abase, for example a tertiary amine, such as triethylamine,tripropylamine, N-methylpyrrolidone and pyridine) with formation of adouble bond (for example in the α-β position). This reaction takesplace, for example, at temperatures of from 30° to 150° C. in an inertsolvent (aromatic hydrocarbons, such as toluene, xylene, andchlorobenzene, or halogenated hydrocarbons, such a methylene chloride orchloroform).

The acyl groups in the compounds of formula I may be split off again bysolvolysis to give the corresponding free hydroxy compounds of formulaI. This solvolytic elimination is carried out, for example, byhydrolysis with dilute acids, or by means of basic substances (potash,soda, aqueous alkali solutions, alcoholic alkali solutions, NH₃) attemperatures of from 10° to 150° C. and more especially at temperaturesof from 20° to 100° C.

Selective elimination is also possible by splitting off only one acylgroup (R₁ or R₂). Selective elimination such as this may be obtained,for example, by reaction of a corresponding diester with alkalihydroxide in a molar ratio of 1:1 at temperatures below 50° C.

The starting compounds of formula II are prepared, for example, byreductive coupling a compound corresponding to the following formula:##STR4## in which R₄ is a C₁ -C₆ alkyl group, particularly the methylgroup, in the presence of titanium trichloride and a complex alkalihydride or the corresponding chloride (in which case the hydroxy groupin formula III is replaced by Cl) with ethylmagnesium bromide in thepresence of cobalt dichloride.

This method of preparing the starting compound II is carried out in asolvent or suspending agent, such as saturated low molecular weightaliphatic or cycloalipathic ethers (dimethoxyethane, diethylether,dioxane, tetrahydrofuran) at temperatures of from 30° to 100° C. Thereaction time is for example between 6 and 18 hours. The reductivecoupling using TiCl₃ is carried out, for example, by initially preparingthe titanium (II)-containing coupling reagent from titanium trichlorideand a complex alkali hydride (for example lithium aluminium hydride) ina suspending agent using the method described by McMurry and Silvestriin J. Org. Chem., Volume 40, No. 18, 1975 for example pages 2687-2688.Suitable suspending agents are saturated, low molecular weight aliphaticor cycloaliphatic ethers, such as dimethoxyethane, diethylether,dioxane, tetrahydrofuran. Suitable complex alkali hydrides are, forexample, alkali borohydrides or alkali aluminium hydrides. Suitablealkali atoms are, for example, lithium and sodium.

The alcohol corresponding to formula III is then added to the suspensionof the titanium (II)-containing coupling reagent in a solvent,particularly an ether of the type mentioned above, and the mixture thusobtained is heated for a prolonged period to a temperature of 93° C.

Where ethylmagnesium bromide is used, the chloride obtained from thealcohol III is for example added dropwise to a solution ofethylmagnesium bromide in a saturated, low molecular weight, aliphaticor cycloaliphatic ether (diethylether, dioxane, tetrahydrofuran) towhich anhydrous COCl₂ has been added. This reaction is preferablycarried out at room temperature (cf. J. Med. Chem., 1981, Volume 24,pages 1192-1197).

The compounds according to the invention show a favorabletumor-inhibiting effect on DMBA-induced mammary carcinomas inSprague-Dawley (SD) rats, on MXT-mammary carcinomas in BD2F₁ -mice andon hormone-dependent prostate carcinomas (Dunning R 3327H).

For example, a dose of 5 mg/kg bodyweight against DMBA-induced mammarycarcinomas in Sprague-Dawley rats produces complete remission in 74% ofthe tumors.

The lowest effective dose in the animal test mentioned above is, forexample,

2 mg/kg oral

1 mg/kg intravenous

1 mg/kg subcutaneous

General dosage ranges for the effect (animal test as described above)are, for example,

5-15 mg/kg oral

3-6 mg/kg intravenous

3-6 mg/kg subcutaneous.

The effect of the compounds according to the invention is comparablewith the effect of the known medicament Tamoxifen.

Indications for which the compounds according to the invention may beconsidered: mammary carcinoma and all oestrogen-dependent tumors (forexample endometrium carcinoma), prostrate carcinoma, benign prostatehyperplasia.

The pharmaceutical preparations generally contain from 25 to 100 mg andpreferably from 40 to 60 mg of the active component(s) according to theinvention.

The active component(s) according to the invention may be administered,for example, in the form of tablets, capsules, pills, dragees,suppositories, ointments, jellies, creams, powders, dusting powders,aerosols or in liquid form. Examples of suitable liquid formulations areoily or alcoholic or aqueous solutions and also suspensions andemulsions.

The production of the medicine can be carried out using the known andcustomary pharmaceutical carriers and diluents as well as othercustomary assistants. These types of carriers and assistants are setforth, for example, in Ullmann's Encyklopadie der technischen Chemie,Volume 4 (1953), pages 1-39; Journal of Pharmaceutical Sciences 52(1963), pages 918 et seq.; H. v. Czetsch-Lindenwald, Hilfsstoffe furPharmazie und angrenzende Gebiete; Phar. Ind. 2 (1961), pages 72 etseq.; Dr. H. P. Fiedler, Lexicon angrenzende Gebiete, Cantor Kg.Aulendorf in Wurttemberg (1971).

Preferred formulations are tablets containing from 40 to 60 mg activesubstance or solutions containing from 5 to 10% active substance.

The individual dose of the active components according to the inventionmay be, for example:

(a) from 40 to 60 mg, preferably 50 mg, in the case of oral formulations

(b) from 20 to 30 mg, preferably 25 mg, in the case of parenteralformulations (for example intravenous, intramuscular)

(c) from 5 to 10%, preferably 7.5%, in the case of formulations forlocal application to the skin and mucous membranes (for example in theform of solutions, lotions, emulsions, ointments, etc.)

(All the doses are based on the free base).

For example, from 1 to 2 tablets containing from 40 to 60 mg activesubstance may be prescribed three times daily or, for example in thecase of intravenous injection, one 10 to 30 ml ampoule containing from20 to 30 mg substance may be prescribed one to three times daily. Withoral administration, the minimum daily dose is for example 50 mg whilethe maximum daily dose should not exceed 400 mg.

In the case of oral application for example, the acute toxicity of thecompounds according to the invention in mice (as expressed by the LD₅₀in mg/kg; Miller and Tainter's method: Proc. Soc. Exper. Biol. a. Med.57 (1944) 261 is above 2000 mg/kg).

The compounds according to the invention are preferably administeredorally and intravenously or even intramuscularly or subcutaneously.

The compositions can comprise, consist essentially of, or consist of thestated materials and the processes can comprise, consist essentially of,or consist of the recited steps with such materials.

DETAILED DESCRIPTION EXAMPLE 12,3-bis-(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane

A solution of 3.34 g (0.01 mole)2,3-bis-(2-fluoro-4-methoxyphenyl)-2,3-dimethylbutane in 250 ml drymethylene dichloride is cooled to -60° C. 7.52 g (0.03 mole) borontribromide are then added to this solution with stirring in a nitrogenatmosphere. After 30 minutes, the freezing mixture is removed and thereaction mixture is kept at room temperature for 4 hours. 50 cm³methanol are then added, the reaction mixture is shaken with 2N NaOH andthe aqueous phase is extracted with diethylether after neutralizationwith 3N HCl. The residue obtained after removal of the ether isrepeatedly recrystallized from benzene.

MP 168°-169° C. (yield: 88%).

Preparation of the starting material:

17.75 g (0.125 mole) methyliodide are dissolved in diethylether and theresulting solution is added dropwise with stirring to 3.04 g magnesiumchips in 15 ml anhydrous ether. The mixture is then heated under refluxfor 30 minutes, followed by the dropwise addition with stirring of asolution of 16.82 g (0.1 mole) 2-fluoro-4-methoxy-acetophenone indiethylether. After heating under reflux for 2 hours, the reactionmixture is cooled, poured onto ice and the corresponding depositdissolved by addition of aqueous NH₄ Cl solution. The ether phase isseparated off, the aqueous phase is extracted with ether, the combinedether phases are washed with aqueous solutions of NaHSO₃, NaHCO₃ andthen with pure water, dried over Na₂ SO₄ and the ether removed.Distillation of the residual oil in a high vacuum gives 14.9 g2-(2-fluoro-4-methoxyphenyl)-2-propanol.

4.63 g (0.03 mole) titanium trichloride are suspended under nitrogen in150 cm³ anhydrous dimethoxyethane (glyme) and 0.38 g (0.01 mole) LiAlH₄rapidly added to the resulting suspension while cooling with ice. Thedark suspension thus obtained is stirred for 10 minutes. 1.84 g (0.01mole) 2-(2-fluoro-4-methoxyphenyl)-2-propanol dissolved in 10 cm³anhydrous dimethoxyethane are then added dropwise with stirring and themixture heated under reflux for 16 hours. After cooling, the reactionproduct is decomposed with 2N HCl, diluted with water and extracted withether. The ether extracts are washed (NaHCO₃, H₂ O) and dried overMgSO₄. After removal of the ether, the2,3-bis-(2-fluoro-4-methoxyphenyl)-2,3-dimethylbutane obtained isrecrystallized from toluene/ligroin.

Example 2 2,3-bis-(2-fluoro-4-acetoxyphenyl)-2,3-dimethylbutane

Acetic acid anhydride (306 mg; 3 mmoles) is added dropwise with stirringto an ice-cooled solution of2,3-bis-(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane (306 mg; 1 mmole)in 30 ml pyridine. The reaction mixture is heated for 3 hours to boilingpoint and hydrolyzed after cooling with ice/H₂ O. After extraction withCH₂ Cl₂, the combined organic extracts are successively washedrepeatedly with 1N HCl, saturated NaHCO₃ solution and H₂ O and driedover MgSO₄. After removal of the solvent in vacuo, the product isrecrystallized from ethanol.

Colorless crystals; Mp. 160°-161° C. (yield: 84%).

Example 3 2,3-bis-(2-fluoro-4-dichloroacetoxyphenyl)-2,3-dimethylbutane

15 ml dry pyridine are added dropwise with stirring and cooling to amixture of 2,3-bis-(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane (1.53g; 5 mmoles) and dichloroacetanhydride (6.0 g, 25 mmoles). After thereaction mixture has been stirred for 30 minutes at room temperature,approximately 150 ml 50% aqueous ethanol are added. The deposit isfiltered off under suction and washed repeatedly with cold 50% aqueousethanol. The product is then carefully recrystallized from ethanol byavoiding excessive heating.

Colorless crystals; Mp. 125.5°-126.5° C. (yield: 40%).

Example 4 2,3-bis-(2-fluoro-4-carbamoyloxyphenyl)-2,3-dimethylbutane

Cyanogen bromide (1.27 g; 12 mmoles) is added while cooling with ice toa solution of 2,3-bis-(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane(1.53 g; 5 mmoles) in 40 ml absolute acetone. Triethylamine (1.21 g; 12mmoles) is added dropwise with vigorous stirring; the temperature shouldnot exceed 10° C. during the addition. After stirring for 10 minutes atroom temperature, the triethylamine hydrobromide precipitated isfiltered off under suction and washed three times with 20 ml acetone.After removal of the solvent is vacuo, the intermediate product obtained(cyanate) is recrystallized from acetone. 30 ml semiconcentrated HCl and2 ml concentrated H₂ SO₄ are added to the cyanate for hydrolysis and themixture is heated for 30 minutes to 1 hour until a pale pink colorationof the solution appears. After rapid cooling, the crude product isfiltered off under suction and washed liberally with water. Thecarbamate is recrystallized from ethanol/H₂ O.

Colorless crystals; Mp. 185.5°-187° C. (yield: 85%, based on thestarting phenol).

Example 5 2,3-bis-(2-fluoro-4-phosphatophenyl)-2,3-dimethylbutane

A mixture of 2,3-bis-(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane (3.06g; 0.01 mole), POCl₃ (7.75 g; 0.05 mole), 2 ml pyridine and 0.1 ml H₂ Ois heated for 5 hours to boiling temperature. Excess POCl₃ is completelyremoved in vacuo. 20 ml H₂ O and 15 g of ice are then added and thephosphorylation mixture is stirred in hot. After stirring for 1.5 hours,the deposit is left overnight to settle and the crude product isfiltered off under suction. The still moist product is suspended inapproximately 15 ml H₂ O and stirred for 1 hour at 20° C. After heatingto 70° C., the product is filtered off hot under suction. The suspensionof the product in 5 ml H₂ O is adjusted to pH 7.8 with 4N NaOH, thetemperature being at most 40° C. The solution obtained is filtered and15 ml of a 5N HCl heated to 80° C. are added over a period of 5 minutes.The crude product thus obtained is filtered off hot and dried in vacuoat 50° C. After the compound has been dissolved in and reprecipitatedfrom methanol/ether, it is recrystallized from H₂ O.

Colorless crystals; Mp. 191°-193° C. (yield: 42%).

EXAMPLES OF PHARMACEUTICAL PREPARATIONS Example for Capsules

10 g 2,3-bis-(2-fluoro-4-hydroxyphenyl)-2,3-dimethylbutane (micronized),106.7 g calcium hydrogen phosphate (Ph.Eur.III) are passed through a 1mm mesh sieve and mixed. The resulting mixture is moistened with asolution of 2.3 g gelatin (DAB 8) and 1.0 g polysorbate (80 Ph.Eur.III)in 20.7 g water, granulated through a 2 mm mesh sieve and dried at 40°C.

The granulate thus obtained is passed with 20 g cornstarch (Ph.Eur.III)through a 0.8 mm mesh sieve and homogenized. In a suitable capsulemachine, this mass is packed in portions of 140 mg in size 3hard-gelatin insertion capsules. 1 capsule contains 10 mg activeprinciple.

Example for Tablets

10 g 2,3-bis-(2-fluoro-4-carbamoyloxyphenyl)-2,3-dimethylbutane(micronized) and 1-7.6 g calcium hydrogen phosphate (Ph.Eur.III) aremixed and moistened with a solution of 2.3 g gelatin (DAB 8) and 0.1 gpolysorbate (80 Ph.Eur.III) in 20.6 g water. The resulting mass isgranulated through a 2 mm mesh sieve and dried at 40° C. The granulatethus obtained, 35 g cornstarch (Ph.Eur.III) and 5 g talcum (Ph.Eur.III)are passed through a 0.8 mm mesh sieve and homogenized. The materialthus obtained is compressed in a suitable machine to form 7 mm diametertablets weighing 160 mg. One tablet contains 10 mg active principle.

DAB 8: Deutsches Arzneibuch (German Pharmacopoeia) 8th edition

Ph.Eur.: European Pharmacopoeia, Volume I, II, or III.

Example for an Injection Solution

18 g sodium chloride for parenteral application (Ph.Eur.I) and 5 g2,3-bis-(2-fluoro-4-phosphatophenyl)-2,3-dimethylbutane are dissolvedunder nitrogen in 1.8 liters water for injection purposes and made up to2 liters with water for injection purposes. Under aseptic conditions,the solution is sterile-filtered through a 0.2 μm pore diameter membranefilter. Finally, sterile 2 ml ampoules are filled under nitrogen with2.15 ml portions of the solution under aseptic conditions. One ampoulecontains 5 mg active principle.

The medication can be used in human medicine or in veterinary medicinealone or in a mixture with other pharmacologically active substances.

The entire disclosure of German priority application No. P 3520622.5 ishereby incorporated by reference.

What is claimed is:
 1. A compound corresponding to the followingformula: ##STR5## in which the substituents R₁ and R₂ are hydrogen, anaminocarbonyl group, a C₁ -C₆ alkylaminocarbonyl group, a di-C₁ -C₆-alkylaminocarbonyl group, the group PO(OH)₂, a C₂ -C₈ alkanoyl group, aC₂ -C₈ halogen alkanoyl group or a C₃ -C₈ alkenoyl group.
 2. A compoundaccording to claim 1 wherein neither R₁ nor R₂ is hydrogen.
 3. Acompound according to claim 1 where both R₁ and R₂ are the groupPO(OH)₂.
 4. A compound according to claim 1 where both R₁ and R₂ arehydrogen atoms.
 5. A compound according to claim 1 where both R₁ and R₂are C₂ -C₈ alkanoyl groups.
 6. A compound according to claim 1 where R₁and R₂ are both C₂ -C₈ halogen alkanoyl groups.
 7. A compound accordingto claim 1 where both R₁ and R₂ are C₁ -C₆ aminocarbonyl groups.
 8. Acompound according to claim 1 where R₁ and R₂ are selected from thegroup consisting of hydrogen, C₂ -C₈ alkanoyl and C₂ -C₈ halogenalkanoyl.
 9. A process for producing a compound corresponding to thefollowing formula: ##STR6## in which the substituents R₁ and R₂represent hydrogen, an aminocarbonyl group, a C₁ -C₆ alkylaminocarbonylgroup, a di-C₁ -C₆ -alkylaminocarbonyl group, the group PO(OH)₂, a C₂-C₈ alkanoyl group, a C₂ -C₈ halogen alkanoyl group or a C₃ -C₈ alkenoylgroup, comprising in a compound corresponding to the following formula:##STR7## in which R₃ is a C₁ -C₄ alkyl group eliminating these two alkylgroups and optionally acylating the resulting compound formula I, inwhich the two substituents R₁ and R₂ are hydrogen by the substituents R₁and R₂ having other than hydrogen, and optionally converting C₃ -C₈halogen alkanoyl groups present in the resulting compounds into C₃ -C₈alkenoyl groups by elimination of hydrogen halide.
 10. A pharmaceuticalcomposition containing a compound according to claim 1 and a carrier,diluent or adjuvant.